Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity.
Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity.
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DOI：
10.1016/j.jaci.2013.04.048
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发表时间：
2013-07
影响因子：
14.2
通讯作者：
Askenase, Philip W.
中科院分区：
文献类型：
--
作者：
Bryniarski, Krzysztof;Ptak, Wlodzimierz;Jayakumar, Asha;Puellmann, Kerstin;Caplan, Michael J.;Chairoungdua, Arthit;Lu, Jun;Adams, Brian D.;Sikora, Emilia;Nazimek, Katarzyna;Marquez, Susanna;Kleinstein, Steven H.;Sangwung, Panjamaporn;Iwakiri, Yasuko;Delgato, Eric;Redegeld, Frank;Blokhuis, Bart R.;Wojcikowski, Jacek;Daniel, Wladyslawa Anna;Kormelink, Tom Groot;Askenase, Philip W.
关键词：
由高剂量反应性半抗原在小鼠中诱导的过敏性皮肤接触敏感性（CS）的T细胞耐受性由释放抗原特异性抑制性纳米囊泡的抑制细胞介导。确定纳米囊泡介导的免疫抑制机制。通过静脉注射与同系红细胞自身抗原缀合的半抗原并随后用相同的半抗原接触免疫来诱导T细胞耐受。收获并培养来自耐受化或对照供体的淋巴结和脾细胞以产生含有抑制性纳米囊泡的上清液，所述抑制性纳米囊泡被分离用于在CS的主动和过继细胞转移模型中进行测试。由于不是Treg的CD 8+抑制性T细胞的上清液中的外来体样纳米囊泡，显示了耐受性。抑制性纳米囊泡的抗原特异性由抗体轻链或可能的全抗体的表面涂层赋予，从而允许将选择的抑制性miRNA-150靶向递送至CS效应T细胞。纳米囊泡也抑制CS在主动致敏小鼠全身注射后，在高峰期的反应。通过耐受产生非抑制性纳米囊泡的泛免疫球蛋白缺陷型JH-/-或miRNA-150-/-小鼠来确定抗体和miRNA-150的作用。这些纳米囊泡可以通过分别添加抗原特异性抗体轻链或miRNA-150来进行抑制。这是通过外泌体样纳米囊泡的系统转运的T细胞调节的第一个实例，所述外泌体样纳米囊泡通过抗体轻链的表面涂层以抗原特异性方式将所选抑制性miRNA递送至靶效应T细胞。
T cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles. To determine the mechanism(s) of immune suppression mediated by the nanovesicles. T cell tolerance was induced by i.v. injections of hapten conjugated to self antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated for testing in active and adoptive cell transfer models of CS. Tolerance was shown due to exosome-like nanovesicles in the supernatant of CD8+ suppressor T cells that were not Treg. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains, or possibly whole antibody, allowing targeted delivery of selected inhibitory miRNA-150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin deficient JH-/- or miRNA-150-/- mice that produced non-suppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively. This is the first example of T cell regulation via systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains.
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